Benzenesulfonyl-semicarbazides and process for their manufacture

ABSTRACT

HYPOGLYCEMICALLY ACTIIVE BENZENESULFONYL - SEMICARBAZIDES OF THE FORMULA   1-((X-QUINOL-8-YL)-CO-NH-Y-),4-(R-NH-CO-NH-SO2-),Z-   BENZENE   WHEREIN X IS HYDROGEN, CHLORINE, BROMINE, METYL OR METHOXY, Y IS -CH(CH3)-CH3-, PREFERABLY   -CH2-CH2-,   Z IS HYDROGEN OR A HYDROCARBON RADICAL OF 1 OR 2 CARBON ATOMS, WHICH FORMS TOGETHER WITH A 5- OR 6-MEMBERED RING, R IS ALKYLENE-IMINO OF 3 TO 7 CARBON ATOMS IN THE RING WHICH MAY BE UNSATURATED OR SUBSTITUTED BY 1 OR 2 METHYL OR LOWER ALKYL OR METHOXY, PENTAMETHYLENIMINO SUBSTITUTED BY ENDOALKYLENE OF 1 TO 3 CARBON ATOMS, HEXAMETHYLENE-IMINO SUBSTITUTED BY ENDOETHYLENE IN B-EPOSITIONS, TETRAHYDRO-ISO-INDOLINE, 4,7 - ENDOALKYLENE-HEXAHYDRO- OR -TETRAHYDRO-ISO-INDOLINE, THE ENDOALKYLENE CONTAINING 1 OR 2 CARBON ATOMS AND THE DOUBLE BOND OF THE TETRAHYDRO COMPOUND BEING IN 5,6 POSITION, AND THE SALTS THEREOF.

3,813,398 BENZENESULFONYL-SEMICARBAZIDES AND PROCESS FOR THEIRMANUFACTURE Walter Aumiiller, Kelkheim, Taunus, Rudi Weyer, Frank- 1furt am Main, and Ruth Heerdt, Mannheim, Germany,

assignors to Farbwerke Hoechst Aktiengesellschaft vormals Meister Lucius& Bruning, Frankfurt am Main, Germany No Drawing. Filed June 3, 1971,Ser. No. 149,746 Claims priority, application Germany, Apr. 26, 1971, P21 20 266.4 Int. Cl. C07d 33/00 US. Cl. 260-283 SA 6 Claims ABSTRACT OFTHE DISCLOSURE Hypoglycemically active benzenesulfonyl semicarbazides ofthe formula wherein X is hydrogen, chlorine, bromine, methyl or methoxy,Y is CH(CH )CH preferably Z is hydrogen or a hydrocarbon radical of 1 or2 carbon atoms, which forms together with Y a or 6-rnembered ring, R isalkylene-imino of 3 to 7 carbon atoms in the ring which may beunsaturated or substituted by 1 or 2 methyl or lower alkyl or methoxy,pentamethylene imino substituted by endoalkylene of 1 to 3 carbon atoms,hexamethylene-imino substituted by endoethylene in 5-6- position,tetrahydro-iso-indoline, 4,7 endoalkylene-hexahydroor-tetrahydro-iso-indoline, the endoalkylene containing l or 2 carbonatoms and the double bond of the tetrahydro compound being in5,6-position, and the salts thereof.

The present invention relates to benzenesulphonyl semicarbazides of theformula in which X represents hydrogen, chlorine, bromine, methoxy ormethyl,

Y represents CH(CH )CH preferably Z represents hydrogen or a hydrocarbonradical having 1 or 2 carbon atoms which forms together with Y a 5- or6-membered ring,

R represents (a) an alkylene-imino radical having 3 to 7 carbon atoms inthe ring, which may be unsaturated or substituted by 1 or 2 methylgroups or a lower alkyl group or a methoxy group,

(b) a pentamethylene-imino radical substituted by an endoalkylene grouphaving 1 to 3 carbon atoms,

(c) a heXamethylene-imino radical substituted by an endoethylene groupin fl-e-POSitiOl'l,

(d) a tetrahydro-isoindoline group, a4,7-endoalkylene-hexahydro-isoindoline group, a4,7-endoalkylene-tetrahydro-isoindoline group, the endoalkylene groupcontaining 1 or 2 carbon atoms and the United States Patent 0 PatentedMay 28, 1974 double bond of the tetrahydro compound being in 5, 6position.

The present invention moreover provides a process for the manufacture ofthese benzene-sulfonyl-semicarbazides, which comprises:

(a) Reacting benzenesulfonamides of the formula 6 0-NHY- Q (c) Reactingbenzenesulfo-chlorides of the formula J with R-substituted ureas,

(d) Hydrolizing benzenesulfonyl-isourea ethers,benzenesulfonyl-isothiourea ethers or benzene-sulfonyl-iminopara-banicacid derivatives substituted by R, Z and (e) Replacing inbenzenesulfonyl-thioureas of the formula the sulfur atom by an oxygenatom, or

(f) Introducing the radical optionally step by step, intobenzenesulfonyl-ureas of the The benzene sulfonyl semicarbazides maythen be treated, optionally for salt formation, with alkaline agents orphysiologically tolerable inorganic or organic acids, i.e., a;pharmaceutically acceptable base or acid.

As semicarbazides or imino-ureas used for the syntheses mentioned sub(a),.. compounds of the formula R-NH-CO-NH or acylated compounds of theformula RNHCONH-acyl are suitable, wherein'acyl preferably stands for alowm'olecular-weight aliphatic or aromatic acid radical, ordiphenyl-semicarbazides of the formula wherein the phenyl radicals maybe substituted or also linked to each other directly or b means of abridge member, such as --CH NH-, -O- or S, or N,N'-di-substitutedcarbohydrazides of the formula RNHCO--NH--R.

As benzenesulfonyl-carbamic acid halides the chlorides are preferablyused.

Moreover, corresponding benzenesulfonyl-ureas which are unsubstituted atthe nitrogen atom of the urea molecule not joined to the sulfonyl groupor which are monoor disubstituted by alkyl or aryl can be converted intothe desired compounds by a reaction with hydrazines of the formula RNHoptionally in salt form. Instead of benzenesulfonyl-ureas carrying suchsubstituents, corresponding N benzenesulfonyl N acyl-ureas,benzenesulfonyl-carbamoyl-imidazoles, -pyrazoles r -triazoles orbis-(benzenesulfonyl)'ureas can also be used, which may carry at one ofthe nitrogen atoms a further substituent, for example methyl. Forexample such bis-(benzenesulfonyl) -ureas or N-benzenesulfonyl Nacylureas may be'treated with hydrazines of the formula RNH and thesalts thus obtained may be heated at an elevated temperature,advantageously at a temperature of at least 80 C.

The imino-carbamic acid esters or benzenesulfonyl-carbamic acid estersmentioned as well as the corresponding thio-csters advantageouslycontain in the ester component a low-molecular-weight alkyl group or aphenyl group. The benzenesulfonyl-isosemicarbazide ethers,benzenesulfonyl-isothio-semicarbazide ethers or benzenesulfonylparabanicacids also mentioned as starting substances can be obtained by reactingcorresponding iso-semicarbazide ethers, isothiosemicarbazide ethers orparabanic acids with corresponding benzenesulfochlorides. Desulfurizingof the benzenesulfonyl-thio-semicarbazides in methanol first also yieldsbenzenesulfonyl-thiosemicarbazide ethers which are then converted intobenzenesulfonyl-semicarbazides by hydrolysis.

As regards the reaction conditions, the variations of carrying out theprocess of the invention may, in general, be modified within wide limitsand can be adapted to each individual case. For example, the reactionsmay be carried out with the use of solvents, at room temperature or atan I elevated temperature.

Depending on the nature of the starting substances, one or other of theaforesaid methods may, in some cases, provide a desired individualcompound of the general formula only in a small yield or may beinappropriate for its synthesis. In such comparatively rare cases, theexpert will have no difficulty in synthesizing the desired productaccording to one of the other methods of the process described.

The benzenesulfonyl-semicarbazide derivatives obtainable according tothe invention are valuable medicaments which have a strong andlong-lasting hypoglycemic action. The hypoglycemic action of theproducts of the in vention can be ascertained by administering them torabbits in a dose of mgJkg. of body weight and determining the bloodsugar level according to the known method of Hagedorn-Jensen or by meansof an autoa'naliz'er for a prolonged period of time.

' For example, it was found that, according to this method, 4- [4-(18 6chloro-quinolino 8 carboxamido "f4 i ethyl)-benzenesulfonyl] 1,1 (3methyl-pentamethylene)-semicarbazide3 hours after administrationbringsabout a lowering of the blood sugar level of 37%, after 24 hours 35% andafter 48 hours still 30%.

The toxicity of the products of the invention is very low and iscomparable to the very well tolerable N-(4- methylbenzenesulfonyl-N-n-butyl-urea.

The products of the invention are preferably used for the manufacture ofpharmaceutical preparations suitable for oral administration and for thelowering of the blood sugar level in the treatment of diabetes mellitus,and may be used as such or in the form of their physiologicallytolerable salts or in the presence of substances which cause such saltformation. For the formation of salts, there may be used, for example,alkaline agents such as alkali metalor alkaline earth metal hydroxidesand alkali metal or alkaline earth metal carbonates or bicar-' bonatesor physiologically tolerable acids.

The present invention also provides a pharmaceutical preparation fororal administration and lowering the blood sugar level in the treatmentof diabetes mellitus, which comprises a compound of the general formulal) or a physiologically tolerable salt thereof in admixture orconjunction with a pharmaceutically suitable carrier;

The pharmaceutical preparations of the invention are preferably made upin the form of tablets and as pharmaceutically suitable carriers theremay be mentioned, for example, talc, starch, lactose, tragacanth andmagnesium stearate.

A pharmaceutical preparation, for example, a tablet or a powder,containing a benzenesulfonyl-semicarbazide of the invention or aphysiologically tolerable salt thereof as the active substance, with orwithout one ormore of the aforementioned carriers, is advantageouslybrought into a suitable dosage unit form. The dose chosen should complywith the activity of the benzenesulfony'l-semicarbazide used and withthe desired effect. Advantageously, the dosage per unit amounts to about0.5 to mg., preferably 2 to 10 mg, but considerably higher or lowerdosage units may also be used, which, when required, are divided ormultiplied prior to their administration.

The following Examples illustrate the invention:

EXAMPLE 1 N [4- (B-quinolino-S -carboxamido-ethyl-ber1zenesulfonyl]-1,1-pentamethylene-semicarbazide 8.3 g. of4-(fl-quinolino-8-carboxamido-ethyl)-benzenesulfonyl-methylurethane(M.P. 207-209" 0., prepared from4-(quinolino-8-carboxamido-ethyl)-benzene-sulfonamide and chloroformicacid methyl ester) were slightly boiled for 1 hour at a descendingcondenser in 100 ml. of dioxan with 2 g. of N-amino-piperidine.Subsequently, the dioxan was entirely evaporated under reduced pressureand the residue was recrystallized from dilute ethanol. The 4[4-(fi-quinolino-8-carboxamido-ethyl) benzenesulfonyl] 1,1pentamethylene semicarbazide obtained melted at 149-l52 C. I

In an analogous manner there were obtained 4-[4-(5-quinolino-8-carboxamido-ethyl)-benzenesulfonyl] 1,1 (3methylpentamethylene) semicarbazide, M.P. 167 C. (from dilute ethanol);7

From 4- (fi-6-chloro-quinolino-S-carboxyamido ethyl)-benzene-sulfonyl-n-ethyl-urethane (M.P. l99-20l C., prepared from 4-(B-G-chloro-quinolino8-carboxamido-ethyl)- benzenesulfonamide andchloroformic acid methyl ester);

4-[4-(fi-6-chloro-quinolino 8 carboxamido ethyl)- benzene-sulfonyl} -l,1-pentamethylene-semicarbazide, M.P.

174-'-l76 C. (from ethanol-dimethylformamide),

4-[4-(fl-6-chloro-quinolino 8 carboxamido ethyl)-benzene-sulfonyl]-1,l-(S-methyl-pentamethylene) semi carbazide, M.P.-497 C. (from ethanol-dimethylformamide), v

4-[4-(fl-fi-chloro-quinolino 8 carboxamido ethyl)-benzene-sulfonyl]-1,1-hexamethylene-semicarbazide, M.P. 188-190 C. (fromethanol-dimethylformamide),

4-[4-(fl-6-chloro-quinolino 8 carboxamido ethyl)-benzene-sulfonyl]-1,1-(3-ethyl pentamethylene) semicarbazide, M.P. 188C. (from ethanol-dimethylformamide);

'From 4-(,8-6-bromo-quinolino-8-carboxamido ethyl)-benzene-sulfonyl-methylurethane (M.P. 202-203 0., prepared from4-(13-6-bromo-quinolino-8-carboxamido-ethyl)- benzene-sulfonamide andchloroformic acid methyl ester):

4-[4-(fl-6-bromo-quinolino 8 carboxamido ethyl)-benzene-sulfonyl]-1,1-pentamethylene-semicarbazide, M.P.

196-197 C. (from methanol-dioxan),

4-[4-(fl-6-bromo-quinolino 8 carboxamido ethyl)-benzene-sulfonyl]1,1-hexamethylene-semicarbazide, M.P. 188-190" C. (frommethanol-dioxan);

From 4-(18-6-methyl-quinolino-8-carboxamido ethyl)-benzene-sulfonyl-methylurethane (M.P. 184-185" C., prepared from 4 (,8 5methyl-quinolino-8-carboxamidoethyl) -benzene-sulfonamide andchloroformic acid methyl ester);

4-[4-(fl-5-methyl-quin0lin0 8 carboxamido ethyl)-benzenesulfonyl1-1,1-(3-methyl pentamethylene) semicarbazide, M.P.170-171" C. (from dilute methanol).

EXAMPE 2 4- [4- fl-quinolino-8-carb oxamido-ethyl )-benzenesulfonyl1-1,1-pentamethylene-semicarbazide 3.7 g. of the sodium salt of 4-(9-quinolino-8-carboxamidoethyl)-benzene-sulfonamide were heated to 100C. for 3 hours with 3 g. of 4,4-diphenyl-1,1-pentamethylenesemicarbazidein 20 ml. of dimethylformamide. After cooling, water was added, themixture was rendered alkaline by means of dilute ammonia and thediphenyl-amine was extracted by shaking it several times with ether. Theaqueous phase was acidified with acetic acid after filtration. Theprecipitated 4-[4-(fl-quinolino-8-carboxamidoethyl)-benzenesulfonyl] 1,1pentamethylene semicarbazide was recrystallized from dilute ethanol andmelted at 149-152 C.

EXAMPLE 3 4-[2-(6-chloro-quinolino-8-carboxamido)-indane 5sulfonyl]-1,1-(4-methyl-pentamethylene) -semicarbazide 4.1 g. of2-(6-chloro-quinolino-8-carboxamido)-indane- S-sulfonamide (M.P. 250 C.)were dissolved in 12 ml. of dimethyl-formamide, the equimolar amount ofsodium hydride was added and the whole was stirred for minutes at roomtemperature. Then 2.0 g. of pyrocarbonic acid ethyl ester were added andafter another 10 to 15 minutes 1.7 g. of N-amino-g-piperidinehydrochloride and 80 ml. of absolute toluene were added. The mixture washeated for 2.5 hours to 120-130 C. with slow distillation. The mixturewas then allowed to cool and suctionfiltered. The filtrate wasconcentrated and the residue was treated with dilute sodium hydroxidesolution and methylene chloride. The alkaline solution was acidifiedwith acetic acid and the precipitated substance was suction-filtered.The unreacted starting compound was separated by preparative thin-layerchromatography using silica gel PF 254. The sulfonyl-semicarbazide couldbe eluted with dimethylformamide. After vaporization of the solvent, thesubstance was dissolved in a solution of sodium carbonatebicarbonate,filtered through charcoal and precipitated by means of HCl.4-[2-('6-chloro-quinolino-8-carboxamido)-indane-5-sulfonyl1-1,1-(4-methylpentamethylene semicarbazide, M.P.219-20 C.-

We claim:

1. A benzenesulfonyl-semicarbazide of the formula in which X representshydrogen, chlorine, bromine, methoxy or methyl, Y represents -CH(CH-)-CH or -CH -CH Z represents hydrogen or an alkylene radical of 1 or 2carbon atoms, which forms together with Y a 5-membered ring, Rrepresents an alkylene-imino radical of 3 to 7 carbon atoms in the ring,which may be unsaturated or substituted by 1 or 2 methyl groups or alower alkyl group or a methoxy group, and the salts thereof of apharmaceutically acceptable base or acid.

2. 4[4-(,B-6-chloro-quinolino 8 carboxamido-ethyl)-benzenesulfonyl}1,1-(3-methyl pentamethylene) semicarbazide.

3. 4-[4-(,8-6-chloro-quinolino 8 carboXamido-ethyD- benzenesulfonyl] -1,l-pentamethylene-semicarbazide.

4. 4-[4-(B-6-chloro-qulnolino 8 carboxamido-ethyD- benzenesulfonyl]-1,1-hexamethylene-sen1icarbazide.

5. 4-[4-(fl-6-chloro-quinolino 8 carboxamido-ethyD-benzenesulfonyl1-1,1-(3-ethyl pentamethylene) semicarbazide.

6. 4-[4-(fl-6-bromo-quinolino-8-carboxamido ethyl)-benzenesulfonyl]-1,1-hexamethylene-semicarbazide.

References Cited UNITED STATES PATENTS 3,655,756 4/1972 Weber et al.260-287 R 3,041,331 6/1962 Wright 260-553 D 3,239,503 3/1966 Korger etal 260-553 D 3,549,645 12/1970 Heerdt et al. 260-553 DA 3,655,756 4/1972Weber et al. 260-553 DA OTHER REFERENCES Ambrogi et al., Arzneim-Forsch,1971, vol. 21, pp. 200- 207.

Kurzcr, Chem. Review, vol. 50, p. 27 (1952).

LEON ZITVER, Primary Examiner G. A. SCHWARTZ, Assistant Examiner

